Adolescent exposure to social stress is associated with a greater incidence of psychiatric and substance abuse disorders, but it is not known how neural mechanisms are altered by adolescent social stress to result in psychopathologies. We have developed a rat model of adolescent social defeat to investigate detrimental effects of teenage bullying, one of the most common social stressors experienced by humans worldwide. As adults, previously defeated rats exhibit decreased medial prefrontal cortex (mPFC) dopamine (DA) tissue content and dampened amphetamine-evoked extracellular mPFC DA release. Adult rats previously exposed to adolescent social defeat also show increased behavioral responses to amphetamine, including greater amphetamine-induced locomotion and a higher preference for amphetamine-associated cues. In this proposal, we will test the hypothesis that mPFC DA hypofunction following adolescent defeat exposure causes heightened amphetamine sensitivity in adulthood. We will also test whether increased amphetamine sensitivity following adolescent social stress can be prevented through pharmacological manipulations delivered at different time points: either (1) by blocking disruption to mPFC DA during the adolescent stress experience, or (2) by restoring mPFC DA activity after stress exposure. The novel use of this animal model to examine these questions provides an innovative means of establishing for the first time a direct link between adolescent stress, mPFC DA function and enhanced sensitivity to drugs of abuse. The proposed research will provide important information for the development of pharmacotherapeutic strategies for treating addiction disorders resulting from exposure to bullying stress in adolescence. Positive findings will also identify the mPFC DA system as an important mediator of adolescent stress-induced behavioral dysfunction. Given the pivotal role of the mPFC in cognition and top-down regulation of emotion, this has broad application for directing potential therapies for disorders that result from adolescent stress beyond addiction. In addition to addressing an important scientific problem, the current proposal will also enrich student research experiences at the University of South Dakota. These studies will provide students with meaningful and high quality early training opportunities in neurobiology, neuropharmacology and behavioral neuroscience in a rural state that is under- represented in terms of federally funded scientific research. The end result will enhance the research training environment at USD and increase the prospects for students from South Dakota to pursue a future career in health-related sciences.